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EP1904051A1 - Bicalutamide adsorbates, process for preparing same, and pharmaceutical compositions thereof - Google Patents

Bicalutamide adsorbates, process for preparing same, and pharmaceutical compositions thereof

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Publication number
EP1904051A1
EP1904051A1 EP06742793A EP06742793A EP1904051A1 EP 1904051 A1 EP1904051 A1 EP 1904051A1 EP 06742793 A EP06742793 A EP 06742793A EP 06742793 A EP06742793 A EP 06742793A EP 1904051 A1 EP1904051 A1 EP 1904051A1
Authority
EP
European Patent Office
Prior art keywords
bicalutamide
adsorbate
adsorbent
process according
mixtures
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06742793A
Other languages
German (de)
French (fr)
Inventor
Klaus GLÄNZER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Karl O Helm AG
Original Assignee
Karl O Helm AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Karl O Helm AG filed Critical Karl O Helm AG
Publication of EP1904051A1 publication Critical patent/EP1904051A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an adsorbate, comprising an adsorbent and bicalutamide adsorbed on said adsorbent, a process for preparing the same, and a pharmaceutical composition thereof.
  • the medicinal substance known by the INN bicalutamide is also known as
  • Racemic bicalutamide can be prepared by known processes, e.g., the ones described or referred to in US 10/498,862 (corresponding to WO 03/097590 A1).
  • Bicalutamide and related acylanilides are compounds exhibiting antiandrogenic activity.
  • a racemic bicalutamide containing drug for the treatment of prostate cancer is marketed under the trade name CASODEX ® (Astra Zeneca).
  • Bicalutamide is sparingly soluble in water and aqueous buffers at various pH values. Furthermore, the speed of being dissolved appears to depend on the particle size of the drug.
  • WO 2004/100944 A1 and US 6,861 ,557 B2 therefore describe the use of micronized bicalutamide in pharmaceutical preparations in order to enhance the speed of dissolution and, hence, the bioavailability of the drug.
  • bicalutamide is reported to crystallize in two different polymorphic forms, called I and II, or to be amorphous (cf. WO 2004/100944 A1). In addition to particle size, the morphology, or changes of the morphology during storage, may affect the drug dissolution profile.
  • micronizing bicalutamide for said pharmaceutical preparations is the application of conventional micronization techniques (various types of mills, sieving procedures, etc.), as disclosed in Liebermann et. al., Pharmaceutical Dosage Forms: Tablets, Vol. 2, 2nd ed., Marcel Dekker, Inc. New York, 1990.
  • all kinds of conventional micronization and sieving procedures require severe protective measures. Particularly potential dust development and cleaning procedures are of high risk.
  • production of pharmaceutical dosage forms from micronized material is very costly since it involves granulation, drying, and sieving steps. Overall, the micronization and sieving steps, as well as the manufacturing of pharmaceuticals from micronized bicalutamide, may lead to significant losses of this expensive and toxic material.
  • the present invention relates to the finding that pharmaceutical compositions containing bicalutamide and exhibiting good drug release properties/profiles can be obtained from certain adsorbates.
  • the present invention is directed to an adsorbate, comprising an adsorbent and bicalutamide adsorbed on said adsorbent.
  • the present invention is directed to a process for preparing an adsorbate, said adsorbate comprising an adsorbent and bicalutamide adsorbed on said adsorbent.
  • the process comprises the steps of providing a suspension of said adsorbent in a solution of bicalutamide and recovering said adsorbate from said suspension.
  • the present invention provides an adsorbate, which can be obtained by the above process.
  • the present invention provides a pharmaceutical composition, comprising an adsorbate according to this invention and optionally pharmaceutically acceptable excipients and/or adjuvants.
  • the present invention provides a process of treating an androgen disorder, comprising administering an effective amount of the pharmaceutical composition of the present invention to a patient in need of such treatment.
  • Figure 1 shows a powder x-ray diffraction pattern of bicalutamide.
  • Figure 2 shows a powder x-ray diffraction pattern of the adsorbate prepared according to Example 2.
  • Figure 3 shows a powder x-ray diffraction pattern of the adsorbate prepared according to Example 3.
  • Figure 4 shows a powder x-ray diffraction pattern of the adsorbate prepared according to Example 4.
  • Figure 5 shows the dissolution profile of CASODEX ® 50mg tablets, Batch No.
  • the present invention provides an adsorbate, comprising an adsorbent and bicalutamide adsorbed on said adsorbent.
  • adsorbate comprising an adsorbent and bicalutamide adsorbed on said adsorbent.
  • bicalutamide is present in a morphologically defined and stable form.
  • the sparingly soluble active compound, bicalutamide is rapidly released.
  • the adsorbate can be prepared in a simple and economical process avoiding the disadvantages described above, in particular avoiding the need of micronization.
  • the adsorbent may preferably be selected from cellulose, cellulose derivatives, polyols, sugars, sugar alcohols and other sugar derivatives, starches, pre-gelatinized starches, starch derivatives, modified starches, dextrins, maltodextrins, polydextroses, dextroses, inorganic excipients, and mixtures thereof.
  • inorganic excipients calcium carbonate, calcium phosphate, calcium sulfate, and mixtures thereof may be exemplified.
  • Preferred adsorbents are microcrystalline cellulose, lactose, mannitol, starch, pre-gelatinized starch, and calcium phosphate, particularly preferred in qualities usually applied for the manufacturing of tablets by direct compression.
  • the adsorbent is selected from direct compressable excipients known to the skilled person.
  • tablets can be prepared from the adsorbate of the present invention by direct compression.
  • direct compressable excipients sugars, polyols, starch products, and mixtures thereof can be exemplified.
  • the weight ratio of bicalutamide to adsorbent is preferably in the range of from 1 :0.1 to 1 :10, more preferably in the range of from 1 :0.5 to 1 :5, and most preferred about 0.8:1.0.
  • the present invention further provides a process for preparing an adsorbate which comprises an adsorbent and bicalutamide adsorbed on said adsorbent.
  • This process comprises the steps of providing a suspension of said adsorbent in a solution of bicalutamide and recovering said adsorbate from said suspension.
  • the solution of bicalutamide can be prepared with a solvent in which the bicalutamide is soluble while the adsorbent should be not soluble or only sparingly soluble in this solvent.
  • a solvent in which the bicalutamide is soluble while the adsorbent should be not soluble or only sparingly soluble in this solvent.
  • at least one organic solvent is used as solvent to prepare the solution of bicalutamide. More preferably, the organic solvent should have a total water content of no more than about 15% by volume, in particular of no more than about 5% by volume.
  • organic solvents suitable in the process of the present invention lower alkanols, such as alkanols having 1 to 4 carbon atoms, ethers, esters, aliphatic ketones, and mixtures thereof can be exemplified.
  • the organic solvent is selected from methanol, ethanol, isopropanol, n-propanol, acetone, ethyl acetate, methyl ethyl ketone, methyl tert-butyl ether (MTBE), acetonitrile, tetrahydrofurane (THF), and mixtures thereof.
  • the suspension of said adsorbent in a solution of bicalutamide can be prepared by either suspending said adsorbent in said solution or dissolving bicalutamide in a suspension of said adsorbent.
  • the solution of bicalutamide is prepared by dissolving the bicalutamide in the solvent to obtain said solution and then the adsorbent is suspended in said solution.
  • the adsorbate can be recovered from the suspension by any suitable means, such as removal of the solvent. Removal of the solvent by for example drying can be promoted by increasing the temperature and/or by applying a vacuum. Equally well, freeze-drying can be used. The solvent can be recovered by working in a closed system and re-used for a subsequent process.
  • adsorbates are obtained which are defined and stable with respect to the morphology of the bicalutamide. Moreover, the adsorbates are characterized by a rapid release of the active ingredient in aqueous solutions and aqueous buffer solutions. According to the invention, a process has been found which, starting from a solution of bicalutamide, leads to adsorbates that are suitable for immediate further processing, without any micronization of the active compound required.
  • Figures 1 to 4 illustrate that in the adsorbates of the present invention, which can be obtained by the above process, bicalutamide is present in a morphologically defined form.
  • Figure 1 shows a powder x-ray diffraction pattern of bicalutamide while figures 2 to 4 show the powder x-ray diffraction patterns of adsorbates of the present invention. From these figures it is evident that the adsorbates contain bicalutamide in a morphologically defined form.
  • the present invention further relates to a pharmaceutical composition, comprising an adsorbate as described above and optionally pharmaceutically acceptable excipients and/or adjuvants.
  • fillers and/or binders for example, celluloses and cellulose derivates (for instance microcrystalline cellulose, native cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), sugars (for instance lactose, fructose, saccharose, glucose, maltose), sugar alcohols (for instance lactitol, mannitol, sorbitol, xylitol), inorganic fillers (for instance calcium phosphates and calcium sulfates), and starches (for instance corn starch, potato starch, wheat starch, dextrins, pregelatinized starches) can be used.
  • celluloses and cellulose derivates for instance microcrystalline cellulose, native cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose
  • sugars for instance lactose, fructose, saccharose, glucose, maltose
  • sugar alcohols for instance lactitol, manni
  • excipients known to those skilled in the art from their general galenic knowledge, such as lubricants, disintegration aids, wetting agents, agents to improve the flow behaviour, alkaline additives, stabilizers, as well as flavours, pigments, and dyes, can be used to prepare the pharmaceutical preparations according to the invention.
  • binders may for example be present in an amount of from 0 to 20% by weight.
  • Fillers and adjuvants may for example be present in the total mixture in an amount of from 20 to 99% by weight, preferably 50 to 99% by weight.
  • the pharmaceutical composition of the present invention may be a unit dosage form, such as capsules, tablets, granules, and pellets.
  • the composition is in the form of a tablet, which is prepared by direct compression.
  • the pharmaceutical preparation of the present invention can be further provided with a common film coating, for instance for controlled release and/or taste masking and/or improved stability. Suitable coatings are known to those skilled in the art.
  • the active ingredient bicalutamide
  • the active ingredient is released essentially similar to marketed tablet formulations.
  • the active ingredient is released such that the pharmaceutical composition of the present invention exhibits a dissolution profile in vitro such that at 15 minutes at least about 50% of the bicalutamide has been released. More preferably, the pharmaceutical composition exhibits a dissolution profile in vitro such that at 30 minutes at least about 75% of the bicalutamide has been released.
  • the present invention provides a process of treating an androgen disorder, comprising administering an effective amount of the pharmaceutical composition described above to a patient in need of such treatment.
  • Dissolution rate 51% after 15 min.
  • the tablets thus obtained may be coated if required.
  • the adsorbate is mixed with excipients, according to the following formulation:
  • Dissolution rate The dissolution profile is shown in Figure 5
  • the adsorbate is mixed with excipients, according to the following formulation:
  • Dissolution rate The dissolution profile is shown in Figure 5
  • the tablets thus obtained may be coated if required.
  • Dissolution rate 50% after 15 min.
  • the tablets thus obtained may be coated if required.
  • Dissolution rate The dissolution profile is shown in Figure 5
  • the tablets thus obtained may be coated if required.

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Abstract

The present invention relates to an adsorbate, comprising an adsorbent and bicalutamide adsorbed on said adsorbent, a process for preparing same, and a pharmaceutical composition thereof.

Description

BICALUTAMIDE ADSORBATES , PROCESS FOR PREPARING SAME , AND PHARMACEUTICAL
COMPOSITIONS THEREOF
FIELD OF INVENTION
[0001] The present invention relates to an adsorbate, comprising an adsorbent and bicalutamide adsorbed on said adsorbent, a process for preparing the same, and a pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION
[0002] The medicinal substance known by the INN bicalutamide is also known as
N-[4'-cyano-3'-trifluoromethyl-phenyl]-3-[4"-fluorophenylsulfonyl]-2-hydroxy-2-methyl- propionamide.
[0003] Racemic bicalutamide can be prepared by known processes, e.g., the ones described or referred to in US 10/498,862 (corresponding to WO 03/097590 A1).
[0004] Bicalutamide and related acylanilides are compounds exhibiting antiandrogenic activity. A racemic bicalutamide containing drug for the treatment of prostate cancer is marketed under the trade name CASODEX® (Astra Zeneca).
[0005] Bicalutamide is sparingly soluble in water and aqueous buffers at various pH values. Furthermore, the speed of being dissolved appears to depend on the particle size of the drug. WO 2004/100944 A1 and US 6,861 ,557 B2 therefore describe the use of micronized bicalutamide in pharmaceutical preparations in order to enhance the speed of dissolution and, hence, the bioavailability of the drug. Moreover, bicalutamide is reported to crystallize in two different polymorphic forms, called I and II, or to be amorphous (cf. WO 2004/100944 A1). In addition to particle size, the morphology, or changes of the morphology during storage, may affect the drug dissolution profile.
[0006] The principle of micronizing bicalutamide for said pharmaceutical preparations is the application of conventional micronization techniques (various types of mills, sieving procedures, etc.), as disclosed in Liebermann et. al., Pharmaceutical Dosage Forms: Tablets, Vol. 2, 2nd ed., Marcel Dekker, Inc. New York, 1990. However, due to the high toxicity of bicalutamide, all kinds of conventional micronization and sieving procedures require severe protective measures. Particularly potential dust development and cleaning procedures are of high risk. In addition, production of pharmaceutical dosage forms from micronized material is very costly since it involves granulation, drying, and sieving steps. Overall, the micronization and sieving steps, as well as the manufacturing of pharmaceuticals from micronized bicalutamide, may lead to significant losses of this expensive and toxic material.
OBJECTS AND SUMMARY OF THE INVENTION
[0007] The present invention relates to the finding that pharmaceutical compositions containing bicalutamide and exhibiting good drug release properties/profiles can be obtained from certain adsorbates. Thus, according to one object, the present invention is directed to an adsorbate, comprising an adsorbent and bicalutamide adsorbed on said adsorbent.
[0008] According to another object, the present invention is directed to a process for preparing an adsorbate, said adsorbate comprising an adsorbent and bicalutamide adsorbed on said adsorbent. The process comprises the steps of providing a suspension of said adsorbent in a solution of bicalutamide and recovering said adsorbate from said suspension.
[0009] According to another object, the present invention provides an adsorbate, which can be obtained by the above process.
[0010] According to another object, the present invention provides a pharmaceutical composition, comprising an adsorbate according to this invention and optionally pharmaceutically acceptable excipients and/or adjuvants.
[0011] According to another object, the present invention provides a process of treating an androgen disorder, comprising administering an effective amount of the pharmaceutical composition of the present invention to a patient in need of such treatment. BRIEF DESCRIPTION OF THE DRAWINGS
[0012] Figure 1 shows a powder x-ray diffraction pattern of bicalutamide.
[0013] Figure 2 shows a powder x-ray diffraction pattern of the adsorbate prepared according to Example 2.
[0014] Figure 3 shows a powder x-ray diffraction pattern of the adsorbate prepared according to Example 3.
[0015] Figure 4 shows a powder x-ray diffraction pattern of the adsorbate prepared according to Example 4.
[0016] Figure 5 shows the dissolution profile of CASODEX® 50mg tablets, Batch No.
26006 (A)1 in comparison with the dissolution profiles of tablets prepared from the adsorbates according to Examples 2 (•), 3 (+), and 5 (G), respectively.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention provides an adsorbate, comprising an adsorbent and bicalutamide adsorbed on said adsorbent. Surprisingly, it has been found that in such adsorbents bicalutamide is present in a morphologically defined and stable form. Moreover, from pharmaceutical preparations prepared with these adsorbates the sparingly soluble active compound, bicalutamide, is rapidly released. Additionally, the adsorbate can be prepared in a simple and economical process avoiding the disadvantages described above, in particular avoiding the need of micronization.
[0018] In the adsorbates of the present invention the adsorbent may preferably be selected from cellulose, cellulose derivatives, polyols, sugars, sugar alcohols and other sugar derivatives, starches, pre-gelatinized starches, starch derivatives, modified starches, dextrins, maltodextrins, polydextroses, dextroses, inorganic excipients, and mixtures thereof. As inorganic excipients calcium carbonate, calcium phosphate, calcium sulfate, and mixtures thereof may be exemplified. Preferred adsorbents are microcrystalline cellulose, lactose, mannitol, starch, pre-gelatinized starch, and calcium phosphate, particularly preferred in qualities usually applied for the manufacturing of tablets by direct compression. [0019] In an advantageous embodiment of the present invention the adsorbent is selected from direct compressable excipients known to the skilled person. In this case tablets can be prepared from the adsorbate of the present invention by direct compression. As direct compressable excipients sugars, polyols, starch products, and mixtures thereof can be exemplified.
[0020] In the adsorbate of the present invention the weight ratio of bicalutamide to adsorbent is preferably in the range of from 1 :0.1 to 1 :10, more preferably in the range of from 1 :0.5 to 1 :5, and most preferred about 0.8:1.0.
[0021] The present invention further provides a process for preparing an adsorbate which comprises an adsorbent and bicalutamide adsorbed on said adsorbent. This process comprises the steps of providing a suspension of said adsorbent in a solution of bicalutamide and recovering said adsorbate from said suspension.
[0022] In the process of the present invention the solution of bicalutamide can be prepared with a solvent in which the bicalutamide is soluble while the adsorbent should be not soluble or only sparingly soluble in this solvent. Preferably at least one organic solvent is used as solvent to prepare the solution of bicalutamide. More preferably, the organic solvent should have a total water content of no more than about 15% by volume, in particular of no more than about 5% by volume.
[0023] As organic solvents suitable in the process of the present invention lower alkanols, such as alkanols having 1 to 4 carbon atoms, ethers, esters, aliphatic ketones, and mixtures thereof can be exemplified. Preferably the organic solvent is selected from methanol, ethanol, isopropanol, n-propanol, acetone, ethyl acetate, methyl ethyl ketone, methyl tert-butyl ether (MTBE), acetonitrile, tetrahydrofurane (THF), and mixtures thereof.
[0024] In the process of the present invention the suspension of said adsorbent in a solution of bicalutamide can be prepared by either suspending said adsorbent in said solution or dissolving bicalutamide in a suspension of said adsorbent. In one embodiment of the invention, the solution of bicalutamide is prepared by dissolving the bicalutamide in the solvent to obtain said solution and then the adsorbent is suspended in said solution. [0025] In the process of the present invention the adsorbate can be recovered from the suspension by any suitable means, such as removal of the solvent. Removal of the solvent by for example drying can be promoted by increasing the temperature and/or by applying a vacuum. Equally well, freeze-drying can be used. The solvent can be recovered by working in a closed system and re-used for a subsequent process.
[0026] With the process according to the present invention, adsorbates are obtained which are defined and stable with respect to the morphology of the bicalutamide. Moreover, the adsorbates are characterized by a rapid release of the active ingredient in aqueous solutions and aqueous buffer solutions. According to the invention, a process has been found which, starting from a solution of bicalutamide, leads to adsorbates that are suitable for immediate further processing, without any micronization of the active compound required.
[0027] Figures 1 to 4 illustrate that in the adsorbates of the present invention, which can be obtained by the above process, bicalutamide is present in a morphologically defined form. Figure 1 shows a powder x-ray diffraction pattern of bicalutamide while figures 2 to 4 show the powder x-ray diffraction patterns of adsorbates of the present invention. From these figures it is evident that the adsorbates contain bicalutamide in a morphologically defined form. The rapid release of bicalutamide from tablets prepared by direct compression of adsorbates of the present invention in admixture with excipients is demonstrated by the dissolution profiles shown in figure 5 in comparison with the dissolution profile of CASODEX® 50 mg tablets.
[0028] The present invention further relates to a pharmaceutical composition, comprising an adsorbate as described above and optionally pharmaceutically acceptable excipients and/or adjuvants.
[0029] All common pharmaceutical excipients can be used to prepare the pharmaceutical preparations. As fillers and/or binders, for example, celluloses and cellulose derivates (for instance microcrystalline cellulose, native cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), sugars (for instance lactose, fructose, saccharose, glucose, maltose), sugar alcohols (for instance lactitol, mannitol, sorbitol, xylitol), inorganic fillers (for instance calcium phosphates and calcium sulfates), and starches (for instance corn starch, potato starch, wheat starch, dextrins, pregelatinized starches) can be used. Furthermore, all other excipients known to those skilled in the art from their general galenic knowledge, such as lubricants, disintegration aids, wetting agents, agents to improve the flow behaviour, alkaline additives, stabilizers, as well as flavours, pigments, and dyes, can be used to prepare the pharmaceutical preparations according to the invention.
[0030] In the total mixture of the pharmaceutical preparation of the present invention binders may for example be present in an amount of from 0 to 20% by weight. Fillers and adjuvants may for example be present in the total mixture in an amount of from 20 to 99% by weight, preferably 50 to 99% by weight.
[0031] The pharmaceutical composition of the present invention may be a unit dosage form, such as capsules, tablets, granules, and pellets. Preferably the composition is in the form of a tablet, which is prepared by direct compression.
[0032] Where necessary for specific applications, the pharmaceutical preparation of the present invention can be further provided with a common film coating, for instance for controlled release and/or taste masking and/or improved stability. Suitable coatings are known to those skilled in the art.
[0033] Surprisingly, from the pharmaceutical preparation of the present invention the active ingredient, bicalutamide, is released essentially similar to marketed tablet formulations. Preferably, the active ingredient is released such that the pharmaceutical composition of the present invention exhibits a dissolution profile in vitro such that at 15 minutes at least about 50% of the bicalutamide has been released. More preferably, the pharmaceutical composition exhibits a dissolution profile in vitro such that at 30 minutes at least about 75% of the bicalutamide has been released.
[0034] Finally, the present invention provides a process of treating an androgen disorder, comprising administering an effective amount of the pharmaceutical composition described above to a patient in need of such treatment.
[0035] The following examples are provided to further illustrate the adsorbates, pharmaceutical compositions, and processes of the present invention. These examples are illustrative only and are not intended to limit the scope of invention in any way. EXAMPLES
[0036] In the examples the following methods of analysis are used:
1. Release of active ingredient (dissolution test) according to USP, method II, 900ml water, 2.0% sodium lauryl sulfate, 37°C, 75rpm, UV detection (270nm).
2. The powder x-ray diffraction patterns were recorded as follows:
Instrument: STADI P transmission diffractometer
Cu Ka1 radiation (l=1.54056A), U=40kV, l=30mA Secondary beam monochromator (flat, graphite)
Detector: Scintillation counter
Aperture: 2 x 8mm, 0.7mm, 0.35mm
Linear PSD: 2Θ=2° to 35°, 5s/0.04° in steps
Sample: Powder, reflection mode
Example 1
Preparation of Bicalutamide Tablets, Formula 1
[0037] To a solution of bicalutamide in acetone (0.08g/ml), the absorbent lactose is added (0.10g/ml) and homogenously suspended. The solvent is removed, using a rotary evaporator, under vacuum and gentle heating. The free flowing adsorbate is finally dried at 35°C for 20 minutes, to remove residual solvent. The adsorbate is mixed with excipients, according to the following formulation:
Bicalutamide-lactose-adsorbate 1 12.5mg
Excipients
(Sodium starch glycolate; povidone; microcrystalline cellulose; magnesium stearate) 20mg
[0038] Suitable amounts of excipients are known to those skilled in the art from their general knowledge, and can be taken from standard references for tablet formulation. [0039] The mixture is directly compressed to tablets, having the following properties:
Compressibility and flowability: good
Mean hardness: 68N
Dissolution rate: 51% after 15 min.
[0040] The tablets thus obtained may be coated if required.
Example 2
Preparation of Bicalutamide Tablets, Formula 2
[0041] To a solution of bicalutamide in acetone (0.08g/ml), the absorbent, a pre-mix of 38% by weight of lactose and 62% by weight of starch is added (0.10g/ml) and homogenously suspended. The solvent is removed, using a rotary evaporator, under vacuum and gentle heating. The free flowing adsorbate is finally dried at 35°C for 20 minutes, to remove residual solvent.
[0042] The x-ray diffraction pattern of the adsorbate is shown in Figure 2.
[0043] The adsorbate is mixed with excipients, according to the following formulation:
Bicalutamide-lactose/starch-adsorbate 112.5mg
Excipients (see Example 1) 20mg
[0044] The mixture is directly compressed to tablets, having the following properties:
Compressibility and flowability: good
Mean hardness: 54N
Dissolution rate: The dissolution profile is shown in Figure 5
[0045] The tablets thus obtained may be coated if required. Example 3
Preparation of Bicalutamide Tablets, Formula 3
[0046] To a solution of bicalutamide in acetone (0.08g/ml), the absorbent pre- gelatinized starch is added (0.10g/ml) and homogenously suspended. The solvent is removed, using a rotary evaporator, under vacuum and gentle heating. The free flowing adsorbate is finally dried at 350C for 20 minutes, to remove residual solvent.
[0047] The x-ray diffraction pattern of the adsorbate is shown in Figure 3.
[0048] The adsorbate is mixed with excipients, according to the following formulation:
Bicalutamide-pre-gelatinized starch-adsorbate 112.5mg
Excipients (see Example 1 ) 20mg
[0049] The mixture is directly compressed to tablets, having the following properties:
Compressibility and flowability: good
Mean hardness: 61 N
Dissolution rate: The dissolution profile is shown in Figure 5
[0050] The tablets thus obtained may be coated if required.
Example 4
Preparation of Bicalutamide Tablets, Formula 4
[0051] To a solution of bicalutamide in acetone (0.08g/ml), the absorbent mannitol is added (0.10g/ml), and homogenously suspended. The solvent is removed, using a rotary evaporator under vacuum and gentle heating. The free flowing adsorbate is finally dried at 35°C for 20 minutes, to remove residual solvent.
[0052] The x-ray diffraction pattern of the adsorbate is shown in Figure 4. [0053] The adsorbate is mixed with excipients, according to the following formulation:
Bicalutamide-mannitol-adsorbate 112.5mg
Excipients (see Example 1) 20mg
[0054] The mixture is directly compressed to tablets, having the following properties:
Compressibility and flowability: good
Mean hardness: 71 N
Dissolution rate: 50% after 15 min.
[0055] The tablets thus obtained may be coated if required.
Example 5
Preparation of Bicalutamide Tablets, Formula 5
[0056] To a solution of bicalutamide in acetonitrile (O.Oδg/ml), the absorbent pre- gelatinized starch is added (0.10g/ml), and homogenously suspended. The solvent is removed using a rotary evaporator under vacuum and gentle heating. The free flowing adsorbate is finally dried at 35°C for 20 minutes, to remove residual solvent. The adsorbate is mixed with excipients, according to the following formulation:
Bicalutamide- pre-gelatinized starch-adsorbate 112.5mg
Excipients (see Example 1 ) 20mg
[0057] The mixture is directly compressed to tablets, having the following properties:
Compressibility and flowability: good
Mean hardness: 64N
Dissolution rate: The dissolution profile is shown in Figure 5
[0058] The tablets thus obtained may be coated if required.

Claims

1. An adsorbate, comprising an adsorbent and bicalutamide adsorbed on said adsorbent.
2. The adsorbate according to claim 1 , wherein the adsorbent is selected from cellulose, cellulose derivatives, polyols, sugars, sugar alcohols and other sugar derivatives, starches, pre-gelatinized starches, starch derivatives, modified starches, dextrins, maltodextrins, polydextroses, dextroses, inorganic excipients, and mixtures thereof.
3. The adsorbate according to claim 2, wherein the inorganic excipient is selected from calcium carbonate, calcium phosphates, calcium sulfate, and mixtures thereof.
4. The adsorbate according to claim 1 , wherein the adsorbate is selected from direct compressable excipients.
5. The adsorbate according to claim 4, wherein the direct compressable excipient is selected from sugars, polyols, starch products, and mixtures thereof.
6. The adsorbate according to claim 1 , wherein the weight ratio of bicalutamide to adsorbent is in the range of from 1 :0.1 to 1:10.
7. The adsorbate according to claim 6, wherein the weight ratio of bicalutamide to adsorbent is in the range of from 1 :0.5 to 1 :5.
8. A process for preparing an adsorbate, said adsorbate comprising an adsorbent and bicalutamide adsorbed on said adsorbent, which process comprises the steps of providing a suspension of said adsorbent in a solution of bicalutamide and recovering said adsorbate from said suspension.
9. The process according to claim 8, wherein the adsorbent is selected from cellulose, cellulose derivatives, polyols, sugars, sugar alcohols and other sugar derivatives, starches, pre-gelatinized starches, starch derivatives, modified starches, dextrins, maltodextrins, polydextroses, dextroses, inorganic excipients, and mixtures thereof.
10. The process according to claim 9, wherein the inorganic excipient is selected from calcium carbonate, calcium phosphates, calcium sulfate, and mixtures thereof.
11. The process according to claim 8, wherein the adsorbate is selected from direct compressable excipients.
12. The process according to claim 11 , wherein the direct compressable excipient is selected from sugars, polyols, starch products, and mixtures thereof.
13. The process according to claim 8, wherein the weight ratio of bicalutamide to adsorbent is in the range of from 1 :0.1 to 1 :10.
14. The process according to claim 13, wherein the weight ratio of bicalutamide to adsorbent is in the range of from 1 :0.5 to 1 :5.
15. The process according to claim 8, wherein said solution of bicalutamide is prepared in at least one organic solvent.
16. The process according to claim 15, wherein the organic solvent has a total water content of no more than about 15% by volume.
17. The process according to claim 16, wherein the organic solvent has a total water content of no more than about 5% by volume.
18. The process according to claim 15, wherein the organic solvent is selected from lower alkanols, ethers, esters, aliphatic ketones, and mixtures thereof.
19. The process according to claim 18, wherein the organic solvent is selected from methanol, ethanol, isopropanol, n-propanol, acetone, ethyl acetate, methyl ethyl ketone, methyl tert-butyl ether, acetonitrile, tetrahydrofurane, and mixtures thereof.
20. The process according to claim 8, wherein bicalutamide is dissolved in a solvent to obtain said solution of bicalutamide and the adsorbent is suspended in said solution.
21. An adsorbate, which can be obtained by the process according to claim 8.
22. A pharmaceutical composition, comprising an adsorbate according to claims 1 or 21 and optionally pharmaceutically acceptable excipients and/or adjuvants.
23. The pharmaceutical composition according to claim 22, wherein said composition is a unit dosage form selected from capsules, tablets, granules, and pellets.
24. The pharmaceutical composition according to claim 23, wherein said composition is a tablet, which is prepared by direct compression.
25. The pharmaceutical composition according to claim 22, which exhibits a dissolution profile in vitro such that at 15 minutes at least about 50% of the bicalutamide has been released.
26. The pharmaceutical composition according to claim 25, which exhibits a dissolution profile in vitro such that at 30 minutes at least about 75% of the bicalutamide has been released.
27. A process of treating an androgen disorder, comprising administering an effective amount of the pharmaceutical composition according to claim 22 to a patient in need of such treatment.
EP06742793A 2005-06-21 2006-05-04 Bicalutamide adsorbates, process for preparing same, and pharmaceutical compositions thereof Withdrawn EP1904051A1 (en)

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US20080045600A1 (en) * 2006-08-17 2008-02-21 Gawande Rahul S Bicalutamide compositions
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DE19814730A1 (en) * 1998-04-02 1999-10-07 Basf Ag Pharmaceutical and cosmetic compositions with matrix containing N-vinyllactam or N-vinylamine based copolymer
MXPA03007641A (en) * 2001-02-27 2003-12-04 Astrazeneca Ab Pharmaceutical formulation.
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US6737550B2 (en) * 2001-06-13 2004-05-18 Biogal Gryogyszergyar Rt. Process for preparing rac-bicalutamide and its intermediates
US7815936B2 (en) * 2001-10-30 2010-10-19 Evonik Degussa Gmbh Use of granular materials based on pyrogenically produced silicon dioxide in pharmaceutical compositions
DE10222104A1 (en) 2002-05-17 2003-12-04 Helm Ag Process for the preparation of N- (4'-cyano-3'-trifluoromethyl) -3- (4 "-fluorophenylsulfonyl) -2-hydroxy-2-methylpropionamide
US20050008691A1 (en) 2003-05-14 2005-01-13 Arturo Siles Ortega Bicalutamide compositions

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